rs41275198

Variant names:

• chr11-2160007-C-T
• rs41275198
• NM_000207.3:c.188-10G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001042376.3(INS-IGF2):​c.187+778G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,576,260 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: INS-IGF2 NM_001042376.3 intron
• Scores: Splicing: ADA: 0.0006472
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.764
• Publications: 2 publications found

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-2160007-C-T is Benign according to our data. Variant chr11-2160007-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.188-10G>A		intron	N/A	NP_000198.1
	INS-IGF2	NM_001042376.3		c.187+778G>A		intron	N/A	NP_001035835.1
	INS	NM_001185097.2		c.188-10G>A		intron	N/A	NP_001172026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.188-10G>A		intron	N/A	ENSP00000370731.5
	INS-IGF2	ENST00000397270.1	TSL:1	c.187+778G>A		intron	N/A	ENSP00000380440.1
	INS	ENST00000250971.7	TSL:1	c.188-10G>A		intron	N/A	ENSP00000250971.3

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00242 AC: 464 AN: 191454 AF XY: 0.00224

Gnomad AFR exome AF: 0.000853

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000755

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00435

GnomAD4 exome AF: 0.00369 AC: 5261 AN: 1423962 Hom.: 17 Cov.: 35 AF XY: 0.00356 AC XY: 2511 AN XY: 705470

African (AFR) AF: 0.000483 AC: 16 AN: 33098

American (AMR) AF: 0.00532 AC: 209 AN: 39264

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25472

East Asian (EAS) AF: 0.00 AC: 0 AN: 38480

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81774

European-Finnish (FIN) AF: 0.0000452 AC: 2 AN: 44276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4950

European-Non Finnish (NFE) AF: 0.00442 AC: 4847 AN: 1097464

Other (OTH) AF: 0.00311 AC: 184 AN: 59184

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74462

African (AFR) AF: 0.000770 AC: 32 AN: 41576

American (AMR) AF: 0.00882 AC: 135 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68004

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00358

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 10 (1)
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)
-	-	1	not specified (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.80
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00065
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41275198; hg19: chr11-2181237;